The present invention relates to a process for preparing aloe-emodin from aloin. Further there is provided a process for preparing rhein and diacerein from aloin.
Diacerein is known as being useful in the treatment of diseases associated with an abnormal degeneration of the connective tissue, and more particularly in the treatment of inflammatory states of the joints and of the connective tissue such as rheumatoid arthritis, osteoarthritis, and osteoporosis, of acute respiratory syndrome in adults, or of pulmonary emphysema.
The most known process for preparing diacerein from aloin comprises acetylation of aloin and subsequent chromic oxidation of the acetylated product to obtain diacerein.
For example, WO-A-98 56750 (Synteco) discloses a process for preparing diacerein from aloin which comprises acetylating aloin to obtain acetylbarbaloin, oxidizing acetylbarbaloin with an oxidizing agent consisting of chromic anhydride in acetic acid solution to obtain crude diacerein and subsequently purifying crude diacerein.
In such a process, the chromic oxidation occurs only if aloin used as the starting material has a high degree of purity.
Further, use of hexavalent chromium compounds such as chromic anhydride (CrO3) is subjected to stringent regulations in view of their very high toxicity and carcinogenicity, as well as on their harmful effect on the environment and at the present time, and in the future authorities may limit the use of hexavalent chromium compounds in the industry.
Still further, to reach a purity of pharmaceutical grade, crude diacerein obtained by chromic oxidation of acetylbarbaloin must be subjected to a subsequent purification process for obtaining a diacerein substantially free from impurities, and more particularly free from aloe-emodin and free from any traces of chromium.
However, purification of crude diacerein to obtain diacerein free from aloe-emodin and free from chromium residues is known to be particularly critical.
Therefore, many processes have been proposed in the literature for purifying crude diacerein obtained by chromic oxidation of acetylbarbaloin (see for example EP-A-0 636 602 (Laboratoire Medidom), WO-A-00/68179 (Synteco), WO-A-98/56750 (Synteco), WO-A-01/96276 (Synteco), WO-A-2004/050601 (Synteco)).
However, known processes for purifying crude diacerein obtained by chromic oxidation of acetylbarbaloin suffer from several drawbacks in that they are complex multi-step processes and/or use toxic solvents or reagents, and/or provoke a remarkable decrease in the yield of pure diacerein with respect to crude diacerein.
As an alternative to preparing diacerein from aloin via the acetylation of aloin to obtain acetylbarbaloin, there have been proposed in the literature processes for the preparation of diacerein starting from aloe-emodin. For example there has been described the preparation of diacerein via oxidation with hexavalent chromium of aloe-emodin (“Sostanze farmaceutiche”, Italian translation and review by R. Longo, OEMF, Milan, 1988, p. 596, of “Pharmazeutische Wirkstoffe, Synthesen, Patente, Anwedungen”, George Thieme Verlag, Stuttgart-New York, 1982-1987).
In the literature there have been described processes for the preparation of aloe-emodin by semi-synthetic preparative processes. Chen When-Ho et al. (Journal of Nanjing College of Pharmacy, 1986, 17(1), 1-4; Chemical Abstract, Vol. 105, 1986, 105:226138z), and U.S. Pat. No. 5,652,265 of Vittori et al., describe the preparation of aloe-emodin by treatment of aloin with FeCl3.
However known processes for the preparation of aloe-emodin suffer from several drawbacks, in that the known synthetic processes require the use of metallic reagents, or other harmful or toxic substances, and require complicated purification processes to remove residues of the metallic or otherwise harmful reagents.